Multidrug resistance (MDR) is a major problem in relapsed lymphomas. Agents which can reverse MDR and chemosensitize are often toxic at effective doses. It would therefore be desirable to develop non-toxic chemosensitizers which act only on tumor cells. We have previously shown that a monoclonal anti-CD19 antibody can reverse P-glycoprotein (Pgp)-mediated MDR in an MDR+ B cell lymphoma in vitro by interfering with the ability of Pgp to efflux drugs from the cells. We now propose to determine how anti-CD19 reverses MDR and whether anti-CD19 can chemosensitize MDR+ lymphoma cells in vivo. If so, we will attempt to lower chemotherapy even further by combining the anti-CD19 with chemotherapy and a targeted immunotoxins (IT) to treat SCID mice with advanced MDR+ lymphoma. The Specific Aims of this competitive renewal proposal are: 1. To continue to elucidate the mechanisms underlying the ability of anti-CD19 to decrease Pgp-mediated MDR in vitro. We will test two hypotheses: i) The function of Pgp is impaired because it is forced out of the low-density lipid microdomains ("lipid rafts") of the plasma membrane (where it is active) after CD19 is crosslinked and enters rafts, and ii) anti-CD19 impairs the function of Pgp by modulating of intracellular ph (pHi) and hence interfering with drug accumulation in cells. 2. To determine whether these MAbs can decrease Pgp-mediated MDR in vivo in SCID/lymphoma mice when administered before or during chemotherapy. 3. To determine the lowest doses of chemotherapy which can be given when both the MDR-reversing MAbs and the MDR-bypassing anti-CD22 IT are co-administered. Taken together, this information should help us determine how to optimize the MAb therapy of MDR+ lymphoma in humans as well as to develop novel ways to use MAbs in conjunction with other conventional and experimental anti-tumor agents.